MMAE-Based Peptide–Drug Conjugates Targeting GPC3 for Precision Chemoradiotherapy in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC), the third leading cause of cancer mortality, lacks effective therapies. Current chemoradiotherapy faces challenges from systemic toxicity and radiation side effects. We developed a series of GPC3-targeting peptide-drug conjugates (PDCs) integrating monomethyl auristatin E (MMAE) to enhance tumor-specific delivery. Among them, PDC <b>22</b> demonstrated efficient tumor cell internalization, drug release, G2/M cell cycle arrest (the most radiosensitive phase), and induced immunogenic cell death of GPC3-positive tumor cells. Mechanistically, PDC <b>22</b> reduced clonogenic survival by increasing γH2AX foci formation, activating DNA damage repair, and blocking cell progression. In xenograft models, PDC <b>22</b> specifically accumulates in tumor regions and significantly delays tumor growth with minimal toxicity. Notably, combining PDC <b>22</b> with radiotherapy resulted in superior tumor control compared with monotherapy, highlighting its potential for precision chemoradiotherapy in HCC. Thus, leveraging GPC3-targeting PDC technology for auristatin delivery with radiotherapy presents a promising therapeutic strategy for HCC.
Authors
- Wenjie Zhang (ORCID: https://orcid.org/0009-0002-4100-844X)
- Fengying Wu (ORCID: https://orcid.org/0000-0001-5129-0528)
- Ding Guofeng
- Kaizhi Li (ORCID: https://orcid.org/0000-0003-1358-620X)
- Cheng Hu (ORCID: https://orcid.org/0000-0001-8666-8471)
- Gang Guo (ORCID: https://orcid.org/0000-0002-4440-6366)
- Hong Yang (ORCID: https://orcid.org/0000-0003-2860-5901)
- Junhua Xu (ORCID: https://orcid.org/0000-0002-8029-201X)
- Xiaomin Zhang (ORCID: https://orcid.org/0000-0002-5660-5303)
- Ning Wang (ORCID: https://orcid.org/0000-0001-7349-9699)
- Yuzhi Li (ORCID: https://orcid.org/0000-0001-9062-8085)
- Yan Zhou (ORCID: https://orcid.org/0000-0003-0757-4341)
- Zhixing Cao (ORCID: https://orcid.org/0009-0006-3375-2745)
- L.X. Sha
- Song Zhou
- Shulei Pan
- Shubo Pan
Institutions
- Anhui Medical University (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Mianyang Central Hospital (CN)
- Key Laboratory of Nuclear Radiation and Nuclear Energy Technology (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Chengdu University of Traditional Chinese Medicine (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00847
- Citations
- 2
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Sichuan Province